Severity of Adverse Reaction* | XALKORI Dosage Modification |
Hepatotoxicity [see Warnings and Precautions (5.1)] |
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN | Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at next lower dosage. |
ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis) | Permanently discontinue. |
Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)] |
Any grade drug-related interstitial lung disease/pneumonitis | Permanently discontinue. |
QT Interval Prolongation [see Warnings and Precautions (5.3)] |
QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms (ECGs) | Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage. |
QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia | Permanently discontinue. |
Bradycardia [see Warnings and Precautions (5.4)] |
Bradycardia† (symptomatic, may be severe and medically significant, medical intervention indicated) | Withhold until recovery to a resting heart rate according to the patient’s age (based on the 2.5th percentile per age-specific norms) as follows: - •
- 1 to less than 2 years: 91 bpm or above
- •
- 2 to 3 years: 82 bpm or above
- •
- 4 to 5 years: 72 bpm or above
- •
- 6 to 8 years: 64 bpm or above
- •
- Older than 8 years: 60 bpm or above
Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications.
If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to the age-specific heart rate provided above.
If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose adjusted, resume at reduced dose upon recovery to asymptomatic bradycardia or to the age-specific heart rate provided above. |
Bradycardia† (life-threatening consequences, urgent intervention indicated) | Permanently discontinue if no contributing concomitant medication is identified.
If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at the second dose reduction level in Table 4 or 5 upon recovery to asymptomatic bradycardia or to the heart rate criteria listed for management of symptomatic or severe, medically significant bradycardia, with frequent monitoring.
Permanently discontinue for recurrence. |
Ocular Toxicity, including Visual Loss [see Warnings and Precautions (5.5)] |
Visual Symptoms, Grade 1 (mild symptoms) or Grade 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living) | Monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disorders. |
Visual Loss (Grade 3 or 4 Ocular Disorder, marked decrease in vision) | Discontinue during evaluation of severe visual loss.
Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss if no other cause found on evaluation. |
Gastrointestinal Toxicity‡ [see Warnings and Precautions (5.6)] |
Nausea (Grade 3: inadequate oral intake for more than 3 days, medical intervention required) | Grade 3 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.§ |
Vomiting (Grade 3: more than 6 episodes in 24 hours for more than 3 days, medical intervention required, i.e., tube feeding or hospitalization; Grade 4: life-threatening consequences, urgent intervention indicated) | Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.§ |
Diarrhea (Grade 3: increase of 7 or more stools per day over baseline; incontinence; hospitalization indicated; Grade 4: life-threatening consequences, urgent intervention indicated) | Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.§ |